Growth of tumors of the mammary gland can be arrested by ovariectomy in most but not all 7,12-dimethyl-benz(alpha)anthracene (DMBA)-induced rat mammary adenocarcinomas. Actual tumor regression in these animals involves production of cyclic adenosine-3',5'-monophosphate (cAMP) and stimulation of cAMP-dependent protein kinase. It has been proposed that a cytoplasmic receptor-kinase (RC) complex is translocated to the nucleus during the initial events leading to tumor regression (1). Data from this laboratory has shown that DMBA-induced rat mammary tumors which fail to regresss after ovariectomy exhibit an excess of free catalytic (C) subunit activity in their cytosols which is not present in the cytosols of either mammary gland or regressing mammary tumor. The mammary tumors which fail to regress are classified as ovarian hormone-independent and exhibit free regulatory (R) subunit activity and a 10-fold lower affinity for cAMP binding than either mammary gland or hormone-dependent (regressing) mammary tumor. Moreover, the hormone-independent mammary tumors fail to accumulate R and C subunit activity in their nuclei. The presence of free R and C subunits in hormone-independent mammary tumor cytosols suggest a failure of an R and C subunit interaction, presumably due to a defective R subunit which may be necessary in order to achieve nuclear translocation of the receptor-kinase (RC) complex. In this proposal, we wish to investigate the phenomenon of cytoplasmic "activation" of the RC complex in regressing rat mammary tumors and determine whether or not cytoplamsic activation of an RC complex may be associated with nuclear accumulation of R and C subunits. Investigation of the occurrence of cytoplasmic receptor activation may provide evidence which may or may not support the concept of nuclear translocation of the receptor-kinase (RC) complex.